Antimicrobial effects of syndiotactic polypeptides

Abstract

We present design and antibacterial studies of stereochemically diversified antimicrobial peptides against multidrug-resistant bacterial pathogens. Syndiotactic polypeptides are polymers of alternating L and D amino acids with LDLD or DLDL backbone stereochemical sequence, which can form stable gramicidin like helical conformations. We designed, synthesized and characterized eight model molecular systems with varied electrostatic fingerprints, modulated through calibrated sequence positioning. Six out of eight model systems showed very impressive antimicrobial activity against three difficult to treat bacterial species, Gentamicin resistant MRSA, E. coli and Mycobacterium. More importantly, the designed LDLD peptides were equally potent in serum, an important drawback of poly L peptide sequences due to enzyme mediated degradation and ion sensitivity. Further, we tested the activity of the designed peptides against drug-resistant clinical isolates of Staphylococcus aureus and Escherichia coli. Molecular dynamics simulation studies suggest formation of an assembly of individual peptides, preceding the membrane interaction and deformation. The activity estimates are comparable with the available peptide based antimicrobials, and are also highly specific and less toxic as per standard estimates. Incorporation of D amino-acids can significantly expand the peptide design space, which can in turn manifest in future biomaterial designs, especially antimicrobials.

A mixed chirality α-helix in a stapled bicyclic and a linear antimicrobial peptide revealed by X-ray crystallography

“…Studies with mixed chirality peptides have shown that they are generally not compatible with α-helical folding, [2][3][4] or form alternative secondary structures such as β-helices, α-strands, various types of β-turns, as well as intermolecular aggregates. [5][6][7][8][9][10][11][12][13] However, α-helical mixed chirality sequences have been directly observed by X-ray crystallography in peptides incorporating the non-natural residue amino-isobutyric acid as α-helix inducer. [14][15][16][17] Incorporation of one or two D-residues in an α-helical L-peptide sometimes preserves helicity, as recently documented by X-ray crystallography for a macrocyclic peptide inhibitor of the p53-MDM2 interaction, 18 and by CD-spectroscopy in a stapled bicyclic peptide inhibitor of the EGF-EGFR complex 19 and a stapled peptide KRAS inhibitor.…”

Quinoline Thiourea-Based Zinc Ionophores with Antibacterial Activity

“…Among the phenyl-substituted thiourea derivatives, the 3,5-bis­(trifluoromethyl) phenyl-substituted thiourea derivative of AQ ( QN5 ) showed modest antibacterial activity against S. aureus (MTCC-96) and GR-MRSA (ATCC 33592) strains (MIC = 3.13 μM or 1.30 μg/mL). In addition, the antibacterial activities of 2-substituted quinoline derivatives were also investigated .…”

“…coli (MTCC 1687) and Gram-positive S. aureus (MTCC-96), drug-resistant bacterial strain GR-MRSA (ATCC 33592; a generous gift from Prof. Vibin Ramakrishnan, BSBE, IIT Guwahati). ,,, Glycerol stocks of the bacterial strains were cultured in agar containing LB (E. coli) and BHI (S.…”

Rational Design of Stapled Antimicrobial Peptides to Enhance Stability and In Vivo Potency against Polymicrobial Sepsis

“…After plating, the lowest concentration at which no growth was observed was recorded as the MBC. For the serum sensitivity assay, the antimicrobial activity of the peptides was tested in medium containing 50% human serum ( 43 , 44 ).…”

“…The mixture was then incubated at 37 ± 2°C for 1 h. Next, the cell suspension was centrifuged at 1,000 × g for 10 min. Percent hemolysis was estimated by the absorbance of treated and control supernatant samples at 540 nm ( 23 , 44 ).…”